Ovarian cancer is the deadliest gynecological disease in the United States, which is due in part to the lack of understanding on how the cancer becomes resistant to chemotherapies. Established (cisplatin) and emerging anti-cancer therapeutics (PARPi) effectiveness rely heavily on intrinsic DNA damage response. Recent reports have observed that cisplatin-resistant cancer cells are cross-resistant to PARP inhibitors. Preliminary experiments in ovarian cancer indicate that aberrant Wnt signaling contributes to resistant to both cisplatin and PARPi by modulating the non-homologous end-joining (NHEJ) pathway. The overall goals of the proposed research is to elucidate the mechanism of Wnt-dependent PARPi/cisplatin resistant in ovarian cancer and to develop a translational approach to re-sensitize tumor cells. During the mentored K99 phase, I will work to clearly establish the impact aberrant Wnt signaling (e.g. loss off Wnt5a) and NHEJ has in conveying or maintaining chemoresistance in ovarian cancer cells. I will then determine the in vivo significance of inhibiting canonical Wnt and NHEJ pathways in the context of resistant disease. I will pursue the establishment of pre- clinical models of ovarian cancer (patient-derived xenograft) to determine if the modulation of Wnt signaling or NHEJ could be translated into the clinical setting to aid in the treatment of chemoresistant ovarian cancer. Excitingly, the proposed work will contribute to the elucidation of the resistant process and could have a direct impact on future therapeutic strategies for ovarian cancer.